16-carbamyl pregnane derivatives



3,257,383 16-CARBAMYL PREGNANE DERIVATIVES Pierre Crabb, Mexico City,Mexico, assignor to Syntex Corporation, Panama, Panama, a corporatio vof Panama N Drawing. Filed Sept. 5, 1962, Ser. No. 221,43

20 Claims. (Cl. 260239.5)

This application is a continuation-in-part of my copending applicationSerial No. 123,673 filed July 13, 1961, now abandoned.

The present invention rel-ates to novel cyclopentanophenanthrenecompounds and to a process for the production thereof.

More particularly, the present invention relates to novel16/8-carbamyl-17a-pregnane, lofi-carbamyl-17}8pregnane,16mcarbamyl-17apregnane and 16acarbamyl-17B-pregnane derivatives. v

The novel compounds of the present invention which are progestationaltype agents with a high anti-ovulatory activity and are alsoanti-estrogenic and anti-androgenic agents are represented by thefollowing formulas:

/\ CON 1 O 3,257,383 Patented June 21, 1966 "ice I CH

In the above formulas Z represents a double bond or a saturated linkagebetween (3-4 and C-5; Y represents a double bond or a saturated linkagebetween 0-5 and C-6; R and R each represent hydrogen, a lower alkyl,amino lower alkyl, lower alkylamino lower alkyl, diloweralkylamino loweralkyl, .aryl or aralkyl group of up to 8 carbon atoms; R and R togetherwith the nitrogen represent a heterocycle such as piperidine,morpholine, piperazine or pyrrolidine which may or may not contain alkylsubstituents; R represents hydrogen or a hydrocarbon carboxylic acylgroup containing less than 12 carbon atoms. The wavy line between C-17and C-20 indicates the a and B configuration for the acetyl side chainand the wavy line at C-16 indicates the 0c and B steric configurationfor the carbamyl moiety.

The acyl group is derived from hydrocarbon carboxylic acids containingless than 12 carbon atoms which may be saturated or unsaturated, ofstraight, branched, cyclic or cyclic-aliphatic, chain, aromatic and maybe substituted by functional groups such as hydroxy, alkoxy containingup to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro,amino or halogen. Typical ester groups are x N mgr,

on, on,

CON CON/ If R1 @Ifi the acetate, propionate, enanthate, benzoate,trirnethyl- TOOOH V T0001 CH CH .-author (C-16a, C-l7B), is different.

acetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate,aminoacetate and fi-chloropropionate.

The novel 16fl-carbamyl compounds of the present invention are preparedby the process illustrated by the above equation:

In the above formulas R, R and R have the same meaning ashereinbeforeset forth; Ac represents the acetyl radical.

In practicing the process outlined above, the starting compound is A-17a-pregnen-3/3-ol-20-one-16fl-carboxylic acid (Romo, Tetrahedron 3,37, 1958). The process of Romo is correct but the configuration assignedby this The configuration (C16fi, C-17oc) assigned later by Mazu-r etal. (Tetrahedron 7, 130, 1959) for this acid is the correctconfiguration. This acid is conventionally acetylated to give the A-17u-pregnen-3fl-ol-20-one-l6fi-carboxylic acid 3-acetate (I) which istreated with a suitable halogenating agent, such as thionyl chloride togive the corresponding acid chloride (II) which upon reaction at roomtemperature and during 18 to 60 hours with ammonia or an amine, such asmethylamine, diethylamine, morpholine, or a lower alkylene diamine,gives the corresponding 16,8-(amino)- carbonyl-A47a-pregnen-3/3-ol-2O-one S-acetate derivative (III: R =aceyl). In orderto obtain the 16/3-(amino)- carbonyl-A 17/3-pregnen-3p-ol-2O-one3-acetate, an excess of reagent is used, and the reaction time isextended to 8 days. The 17,8-isomer may also be obtained by a longalkaline treatment, such as for example, by treatment of the1706-COH'1POI1I1d with potassium hydroxide in methanol solution, for aperiod of time in the order of 2 days.

Upon partial saponification of the 3-acetate derivatives in a mildalkaline medium, such as potassium carbonate solution, there areobtained the corresponding free 3/3- hydroxyl compounds (III: R=hydrogen).

The 165- (amino) -carbonyl-A -17a-pregnene-3 ,ZO-dione derivative (IV)as well as the 17fi-isomer are prepared by reaction of the 'known16,8-carboxy 17-isoprogesterone (Romo, Tetrahedron 3, 37, 1958) withoxalyl chloride followed by a reaction with ammonia or an amine, such Img; ,1 009K.

I ll 0 R VIII Y alkylene diamine. This derivative is hydrogenated to therespective 16,8-(amino)-carbonyl-17aallopregnane 3,20- dione derivative(V).

Upon hydrogenation of the 16,B-(amino)-carbonyl-A 17cc pregnen 3/3-.ol-20-one, and its 17,8-isomer (III: R =hydrogen), there are producedthe 16fl-(amino)-carbonyl 17u-allopregnan-3 8-ol-20-one derivative andthe corresponding l7/8-isomers (VI: R hydrogen).

.The above obtained compounds with a secondary hydroxyl group areconventionally acylated in pyridine with an acylating agent, as forexample acetic anhydride, propionic anhydride or benzoyl chloride, togive the corresponding 3B-acyloxy derivatives (III and VI: R =acyl).

The novel 16a-carbamyl-17 3-pregnane derivatives of the presentinvention are prepared in accordance with the following scheme:

In the above formulae R, R and R have the same meaning as hereinbeforeset forth; R may be hydrogen or lower alkyl.

In practicing the process outlined above, the starting A pregnene 3B20/3 diol 16a-carboxylic acid (VI: R =R =H) is treated with diazomethanein a solvent in ert to the reagent, such as methylene chloride-ether,for a period of time of the order of 18 hours, thus giving A pregnene 38,20,B-diol-16a-carboxylic acid methyl ester (VI: R =H, R =rnethyl),which upon selective acetylation with approximately 1 molar equivalentof acetic anhydride in pyridine at about 0 C., yields A -pregnene-35,20,8-diol-16a-carboxyli-c acid methyl ester 3-acetate (VI: R =acetyl;R =methyl). Conventional Oppenauer oxidation of the latter steroidaffords A -pregnen-3fl-ol- 20-one-16a-carboxylic acid methyl esteracetate (VII: R =acetyl; R =methyl), which is hydrolyzed conventionallyin a basic medium to give A -pregnen-3fl-ol-20- one-16zx-carb0xylic acid(VII: R =R =H). Conventional acylation of the latter, as by treatmentwith acetic anhydride in pyridine, yields the corresponding A -pregnen3B ol 20 one-l6a-carboxylic acid acylate (VII:

R =acyl; R =H), which is treated with oxalyl chloride,-

under anhydrous conditions, preferably at reflux temperature for aperiod of time of the order of 2 hours, thus furnishing thecorresponding acylate of M-pregnen-Sfl-ol 20-one-16a-carboxylic acylchloride, which upon reaction, at room temperature and during 1 to 60hours, with ammonia or an amine, such as methylamine, diethylamine,morpholine, or a lower alkylene diamine gives'the corresponding 16a(amino)carbonyl-A -pregnen-3,8-ol-2O-one 3-acylate (VIII: R acyl; Ydouble bond). The last named acylate is conventionally saponified in amild alkaline medium, as for example potassium carbonate in methanol togive the corresponding free 3-alcohol (VIII: R =H; Y=double bond). Thel6a-(amino)carbonyl-A pregnen-EvB-ol-ZO-one derivatives of the presentinvention (III: Y=double bond) upon hydrogenation in the presence of asuitable catalyst, as for example 5% palladium on charcoal, .yield thecorresponding 16a-(amino)carbonyl-allopregnane-3,20-dione (VIII:Y=saturated linkage).

Following a second sequence of reactions, A -pregnene-35,20,8-dio1-l6a-carboxylic acid methyl ester (VI: R =H;

R =methyl) is treated under conventional Oppenauer conditions to give'A-pregnene-3,20-dione-16a-carboxylic acid methyl ester (IX: R =methyl)which is conventionally hydrolyzed in a basic medium to the free acid(IX: R =H). Treatment of the latter acid with a sodium hydroxidesolution, followed by reaction of the resulting sodium salt with oxalylchloride gives the corresponding acyl chloride (X), which upon reactionwith ammonia or an amine, such as methylamine, diethylamine, morpholineor a lower alkylene diamine gives the corresponding 1604- (amino)carbonyl-A -pregnene-3,20-dione (XI: Z double bond). The latter A-pregnene-3,20-dione derivative is hydrogenated in the presence of asuitable catalyst, such as 5% palladium on charcoal, to produce thecorresponding 16a (amino)carbonyl-allopregnane-3,20-dione (XI:Z=saturated linkage). r

The novel l6a-carbamyl-l7a-pregnane derivatives of the present inventionare prepared in accordance with the process illustrated asfollows:

XVI

In the above formulas R, R R and R have the same meaning as specifiedhereinbefore.

In practicing the process just outlined, the starting 16pcarboxy-A-17u-pregnen-3B-ol-2O-one (XII) is treated with acetic anhydride inpyridine, at steam bath temperature, for a period of time of the orderof 5 hours, thus yielding A -17a-pregnadiene-3fl,2O-diol-16a-carboxylicacid lactone (XIII), which upon hydrolysis in a very mild alkalinemedium such as potassium bicarbonate in water-dioxane, at refluxtemperature for a period of time of the order of 2 hours affords theacetate of A -l7ot-pregnene-3fl-ol- 20-one-16a-carboxylic acid (XIV: R=acetyl; R =H). Treatment of the latter acid with oxalyl chloride underanhydrous conditions, preferably at reflux temperature for a period oftime of the order of 2 hours, yields the corresponding 16a-carboxylicacyl chloride which is treated with ammonia or an amine, such asmethylamine, diethylamine, morpholine, or a lower alkylene dioamine,preferably at room temperature and during 1 to hours, thus giving thecorresponding 16t-(amino)-carbonyl- A -l7a-pregnen-3B-ol-20-one3-acylate (XV: R =acyl; Y=double bond). The latter a-cylate may beconventionally saponified in a mild alkaline medium to give thecorresponding free 3-alcoho1 (XV: R =H; Y=double bond). The l6a-(amino)-carbonyl-A -17a-pregnen-3/3-ol- ZO-one derivatives described heretofore(XV: Y=double bond) are treated in a hydrogen atmosphere, in thepresence of a suitable catalyst, such as 5% palladium on charcoal, togive the corresponding 16a-(amino) -carbony1-1|7a-allopregnan-BB-ol-ZO-one derivatives (XV: Y=saturated linkage).

Following a secondsequence of reactions, the acetate of A-17a-pregnen-3B-0l-20-one-16a-carboxylic acid (XIV: R =acetyl; R :H) ishydrolyzed in a basic medium, such as potassium carbonate in water, togive the free 3-alcohol (XIV: R =-R =H) which upon conventionaltreatment with diazomethane yields A -l7a-pregnen-3fi-ol-2O-one-16a-carboxylic acid methyl ester (XIV: R =H;

R =methyl). The latter A -17u-pregnen-3B-ol is conventionally treatedunder Oppenauer conditions to pro- XIV is hydrogenated in the presenceof a suitable catalyst, such as 5% palladium on charcoal, to produce thecorresponding 16a-(amino)-carbonyl-l7u-allopregn-ane 3,20 dione (XVII:Z=saturated linkage).

The following specific examples serve to illustrate but are not intendedto limit the scope of the present invention:

EXAMPLE I To a solution of 3 g. of A-pregnene-3fl,20fl-diol-16acarboxylic acid (Mazur et al. Tetrahedron 7,130 (1959)) in 50 cc. of methylene chloride were added an excess ofdiazomethane in ether (obtained from nitroso methylurea) and a few dropsof methanol. The reaction mixture was kept at room temperature for 1.8hours. The excess reagent was decomposed with acetic acid. The resultingmixture was poured into water, the organic layer washed to neutral andevaporated to dryness. Recrystallization from acetone-hexane affordedM-pregnene-SBflOfl-diol- 16a-carboxylic acid methyl estr.

EXAMPLE II A solution of l g. of the latter ester in 80 cc. of tolueneand 20cc. of cyclohexanone was dried by distilling oif 10 cc. of thesolvent. A solution of 1 got aluminum isopropoxide dissolved in 7 cc. ofanhydrous toluene was then added and the mixture was refluxed for 45minutes; 4 cc. of acetic acid were added and the solvents removed bysteam distillation. The product was extracted several times with ethylacetate and the organic extracts washed with 5% hydrochloric acidsolution, water, 10% sodium carbonEte solution and water until neutral,dried over anhydrous sodium sulfate and evaporated to dryness.Crystallization from acetone-hexane afforded A -pregene-3,20-dione-16a-carboxylic acid methyl ester.

EXAMPLE III A mixture of 1 g. of A -pregnene-3fl,20B-diol-16a-carboxylicacid methyl ester, 4 cc. of pyridine and 1.05 molar equivalents ofacetic anhydride was kept at C. overnight, poured into ice Water, theformed precipitate was filtered, washed with water and dried.Crystallization from acetone-hexane gave A-pregnene-3B,20/3-diol-16acarboxylic acid methyl ester 3-acetate.

EXAMPLE IV The latter compound was treated in accordance with Example IIthus giving A -pregnen-3/3-ol-20-one-16u-carboxylic acid methyl esteracetate.

EXAMPLE V A suspension of 1 g. of the latter steroid in 60 cc. ofmethanol was treated with a solution of 1 g. of potassium carbonate in 6cc. of water; the mixture was boiled under reflux for 1 hour, thenacidified with dilute hydrochloric acid and extracted with methylenechloride. The extract was washed with water, dried over anhydrous sodiumsulfate and evaporated to dryness thus giving A -pregnen-3B-ol-20-one-16a-carboxylic acid.

When applying the same procedure to A -pregnene-3,20-dione-16u-carboxylic acid methyl ester, there was produced the free A-pregnene-3,20-dione-l6a-carboxy1ic acid.

8 EXAMPLE v1 A -pregnene 3,8 ol 20 one-16a-carboxylic acid was treatedin accordance with Example III, thus yielding A-pregnen-3B-ol-20-one-l6a-carboxylic acid acetate.

EXAMPLE VII 1 g. of A -pregnen-3/3-ol-20-one-16a-carboxylic acid acetateand 5 cc. of oxalyl chloride was refluxed under anhydrous conditionsduring 2 hours. The solution was evaporated in vacuum, 10 cc. of drybenzene were added and reevaporated to eliminate traces of oxalylchloride, thus affording the acetate of A-pregnen-3fi-ol-20-onel6a-carboxylic acyl chloride. The latter crudeacyl chloride was treated with 2 cc. of diethylamine in 50 cc. ofbenzene. The reaction mixture was left overnight at room temperature,then an aqueous solution of sodium carbonate was added. The resultingemulsion was extracted with ether, the extract dried over sodium sulfateand'evaporated to dryness. Crystallization from methanol-water afforded16a-(diethylcarbamyl)-A -pregnen 3B-ol-20-one acetate.

EXAMPLE VIII 1 g. of A -pregnen-3 8-ol-20-one-16u-carboxy1ic acidacetate was treated following the technique described in Example VIIexcept that diethylamine was substituted by piperidine thus affording16a-(piperidino-carbonyl)-A pregnen-3B-ol-20-one acetate;

EXAMPLE IX 1 g. of A -pregnen-3fi-ol-20-one-16a-carboxylic acid acetatewas treated in accordance with the method described in Example VII,except that diethylamine was substituted by morpholine thus furnishing16u-(morpholinocarbonyl)-A -pregnen-3B-ol-20-one acetate.

EXAMPLE X 1 g. of A -pregnen-3B-ol-20-one-1a-carboxylic acid acetate wastreated with oxalyl chloride in accordance with Example VII. Thel6u-carboxylic acid chloride thus obtained was dissolved in 50 cc. ofbenzene and 5 cc. of ammonium hydroxide were added. The reaction mixturewas kept at room temperature for 1 hour. The formed precipitate wasfiltered off, washed with benzene and dried under vacuum.Recrystallization from methanol-water afforded 16a-carbamyl-A-pregnen-313-01-20- one acetate.

EXAMPLE XI 1 g. of the acetate of A -pregnen-3B-ol-20-one-16acarboxylicacyl chloride, obtained according to Example VII, was dissolved in 50cc. of benzene and treated with 5 cc. of N, N'-diethyl-arninoethylamineand the reaction mixture was left for 60 hours at room temperature. Theproduct was isolated following the usual procedure, thus giving16a-(N,N-diethylamine-ethyl-carbamyl)-A -pregnen-3fi-ol-20-one acetate.

EXAMPLE XII l g. of A -pregnen-3B-ol-20-one-16a-carboxylic acid acetatewas treated in accordance with the method described in Example VII,except that diethylamine was substituted by N-methyl aniline thusyielding l6cx-(N- methyl-N-phenyl-carbamyl)-M-pregnen-3B-ol-20-0neacetate.

' EXAMPLE XIII 3 g. of l6a-carbamyl-n pregnen-3fi-ol-2O-one acetate incc. of methanol were treated with 1 g. of potassium carbonate in 5 cc.of water. The mixture was refluxed for 0.5 hours, then poured into icewater, the precipitate collected, washed with water, and dried, thusproducing a crude product which upon recrystallization from methylenechloride-ether afforded l6a-carbamyl-A pregnen-3fi-ol-20-one.

When applying the above method to: 16a-(diethyl carbamyl) -A-pregnen-3B-ol-20-one acetate, 16a- (piperidino carbonyl -A-pregnen-3B-ol-20-one acetate,

. 160t-(I'IIOI'PhOlII10- carbonyl)-M-pregnen-3B-ol-20-one acetate,16a-(N,N'-diethylamino ethyl carbamyl)-A -pregnen- 3,8-ol-20-oneacetate, and 16a-(N-methy1-N-phenyl carb amyl) -A -pregnen-3 {3-01-20-one acetate there were respectively obtained: l6ot-(diethylcarbamyl)-A -pregnen-3fl-ol-20 -one, 1611- (piperidino carbonyl) -A-pregnen-3 /iol-20-one, Mot-(morpholino carbonyl)-A-pregnen-3B-oI-ZO-one, l6a-(N,N diethylamino-ethyl-carbamyl)-A -pregnen-3fl-ol-20-one, and 16a-(N-methyl-N-phenyl carbamyl) -A -pregnen-3B-ol-20-one.

EXAMPLE XIV To a solution of 2.4 g. of A -pregnene-3,20-dione-16otcanboxylic acid in 360 cc. of ethyl alcohol, 67.5 cc. of0.1 N sodium hydroxide solution were added. This mixture was evaporatedto dryness under high vacuum and then dried, under high vacuum, at 110during 1 hour. Then 50 cc. of anhydrous benzene and 25 drops ofanhydrous pyridine were added, at room temperature. After cooling thissolution at 0, cc. of oxalyl chloride were added with stirring. Themixture was allowed to react during 3 hours at 0. The solvents were thenevacuated under high vacuum. To this dry material 60 cc. of anhydrousbenzene were added and then, drop by drop, at 0, 80 cc. of ammoniumhydroxide were added with stirring. This mixture was allowed to reactfor 3 hours at 0 and 'hours at room temperature. Extraction with ethylacetate followed by a chromatography on silica gel yielded a productwhich was recrystallized from methanol-water to give 16e-carba'myl-A-pregnene-3,ZO-dione.

The foregoing procedure was repeated, except that ammonium hydroxide wassubstituted by diethylamine, piperidine, monpholine,N,N-diethylaminoethylamine, and N-methyl aniline, thus affordingrespectively l6oc-(diethyl carb amyl) -A -pregnene-3 ,4-di0i16, 16:1-(piperidino carbonyl) -A -pregnene-3,20-dione, 160c-(morpholino-carbonyl) A -pregnene-3,20-dione,t16a-(N',N'-diethylaminoet-hyl-carbamyl)-A -pregnene-3,2O-dione, and16a-(N- methyl-N-phenyl carbamyl)-A -pregnene-3,20-dione.

EXAMPLE XV A solution of 1 g. of 16a-car1bamyl-A pregnene-3,20- dione in50 cc. of ethyl acetate was shaken with 50 mg. of 5%palladium-on-charcoal catalyst in a hydrogen atmosphere, until the gasuptake corresponded to one mol. The catalyst was filtered off and thefiltrate evaporated to dryness. Recrystallization fromrnethanol afforded16ozcarbamyl-allopregnane-3,20-dione.

The rest of the products obtained in Example XIV were treated by thesame procedure, thus yielding respectively:

IGu-(diethyl carbamyl)-allopregnane-3,20-dione, 16a- (piperidinocarbonyl)-allopregnane-3,20-dione, 16a-(morpholinocarbonyl)-allopregnane-3,20-dione, 16oc-(N',N'- diethylaminoet-hylcarbamyl) allopregnane-3,20-dione, and 16a-(N-methyl-N-phenylcarbamyl)-allopregnane-3, ZO-dione.

EXAMPLE XVI The procedure described in Example XV was applied to:

L-( diethyl carb amyl) -allopregnan-3 3-ol-20-one,

16w (piperidino carbonyl) -allopregnan-3fi-ol-ZO-one,

1505-(11101131'1011110 carbonyl) -allopregnan-3fl-ol-20-one,

16a-(N,N-diethylaminoethyl carbamyl)-allopregnan 3,8-ol-20-one, and

161x- N-methyl-N-phenyl canbamyl -allopregnan- 3p-o1-20-one.

EXAMPLE XVII 1 g. of 16a-carbamyl-A -pregnen-3fl-ol-20-one, in 5 cc. ofpyridine was treated with 1 cc. of propionic anhydride. The reactionmixture was left overnight at room temperature, then poured into icewater, the formed precipitate filtered off, washed with water and dried.Recrystallization from acetone-hexane afforded 16ot-carbamyl-A-pregnen-3fi-ol-20-one propionate.

When applying the same procedure toMot-carbamylallopregnan-3fl-ol-20-one, there was obtained16a-carbamyl-allopregnan-3,8-ol-20-one, propionate.

EXA'M'PL'E XVIII 3.5 'g. of 16fi-carboxy-A M1.7ot-pregnen-3fl-ole20-one(Mazur et al. V. supra) were dissolved in 25 cc. of pyridine and 10 cc.of acetic anhydride were added. The mixture was heated on the steam bathfor 5 hours, then left overnight at room temperature. There was addeddilute hydrochloric acid and the \product was extracted with ethylacetate. The extract was washed with water to neutral, dried overanhydrous sodium sulfate and evaporated to dryness. l iecrystallizationafforded the 3-acetate of the A-17a-pregnadiene-SB-ZO-diol-16a-canboxylic acid lactone.

EXAMPLE XIX To a solution of 1 g. of the latter lactone in 300 cc. ofdioxane were added 700 mg. of potassium bicarbonate dissolved in 50 cc.of water. The resulting mixture was refluxed for 2 hours, then acidifiedwith dilute hydrochloric acid and extracted with methylene chloride. Theextract was washed with water, dried over sodium sulfate and evaporatedto dryness. Recrystallization from methanol-water yielded the acetate ofA -17a-pregnen-3fi-ol- 20-one-16m-carboxylic acid.

EXAMPLE XX The latter 16a-carboxylic acid was treated successively inaccordance with Examples V,.I, and II, yielding respectively: A47a-pregnen-3p-ol-20-one-16a-carboxylic acid, methyl ester and A-17a-pregnene-3,-2O-dione-16m-carboxylic acid methyl ester.

EXAMPLE xxr The latter methyl ester was hydrolyzed in accordance withExample V, thus giving: A -17a-pregnene-3,20-dione- 16u-carboxylic acid.

EXAMPLE XXII The acetate of A -l7a-pregnen-3fi-ol-20-one l6a-carboxylicacid was treated in accordance with Examples VII, VIII, IX, X, XI andXII thus giving respectively:

16t1- diethyl carbamyl) -A -17u-pregnen-3B-ol-20'-one acetate,

loot-'(piperidino carbonyl)-A -17ot-pregnen-3l3-ol-20-one acetate,

160t-(mO1'PhO1iI1O carbonyl) -A -17a-pregnen-3fi-ol- 20-one acetate,

16a-carbamyl-A -17a-pregnen-3fi-ol-20-one acetate,

16w N','N '-diethylaminoethyl canbamyl) -A 1 7a-pregnen-3fi-ol- 20-oneacetate, and

16a-(N-methyl-N-phenyl carbamyl) -A -17a-pregnen- 3 fi-ol-20-oneacetate.

EXAMPLE XXIII 16a (diethyl carbamyl)-A -17a-pregnen-3 fi-ol-20-oneacetate was treated in accordance with Example XIII,

' 20-dione.

I I thus furnishing 16a-(diethyl carbamyl)-A -17ot-pregnen- 3fi-ol-20-one.

The rest of the compounds disclosed in Example XXII were saponified bythe same procedure, thus affording the corresponding free alcohols.

EXAMPLE XXIV The final products of Example XXII were treated inaccordance with Example XV, thus yielding respectively: l6a-(diethyl.carbamy-l) -l7a-allopregnan-313-ol-20-one acetate, 16u-(piperidinocarbonyl)-17ot-allopregnan-3B-ol-20- one acetate, 16OL-(II1OTphOllHOcarbonyl)- l7a-allopregnan- 3fl-ol-20-one acetate, l 6otcarbamyll7a-allopregnan-3fl-ol- 20-one acetate, 16w(N',Nf-diethylaminoethylcarbamyl)- 17a-allopregnan-3fl-ol-20-one acetate, and 16zx-(N-methyl-N-phenyl carbamyl) -l7a-allopre-gnan-3fi-ol-20-one acetate.

EXAMPLE XXV A -l7a-pregnene-3,ZO-dione-16a-carboxylic acid was treatedin accordance with Example XIV, thus furnishing: 16a ca-rb amyl-A-l7aapregnene-3,20-dione, l6zx-(diethyl carbamyl) -A-l7owpregnene-3,20-dione, l6tx-(piperidino carbonyl) -A-l7ot-pregnene-3,2O-dione, 16a-(morpholino carbonyl) -A-17a-pregnene-3,2O-dione, 16a-(N',N'-diethylaminoethyl carbamyl)-A-l7aapregnene-3,20-dione, and IGa-(N-methyLN-phenyl carbamyl)-A-17ot-pregnene-3,

EXAMPLE XXVI The compounds obtained in Example XXV were treatedaccording to Example XV, thus giving respectively: 160ccarbamyl 17aa-llopregnane-3,20-dione, 16x-(diethylcarbaimyl)-l7et-allopregnane-3,20-dione, 16zx-( piperidino carbonyl)-17a-allopregnane-3,20-dione, 16a-(morpholinocarbonyl)-17a-allopregnane-3,ZO-dione, 16u-(N',N-diethylaminoethylcarbamyl)-17a-allopregnane-3,20-dione, and 16a-(N methyl-N-phenylcarbamyl) -l7ot-allopregnane-3, 20-dione.

EXAMPLE XXVII 16u-carbamyl-l7a-allopregnan-3fi-ol-ZO-one acetate wastreated successively according to Examples XIII and XV II thus givingrespectively '16a-carbamyl-17ot-allopre1gnan- 3B-ol-20-one and16a-carbamyl-17a-allopregnan-35-ol-20- one propionate.

EXAMPLE XXVIII.

1 g. of A -l7apregnen-3B-ol-20-one-l6p-carboxylic acid 3-acetate (M.P.208210; [ab 95 (CHCl prepared by conventional acetylation with aceticanhydride in the presence of pyridine of A -17ot-pregnen-3fl-ol-20-one-16pcarboxylic acid (Romo, Tetrahedron, 3,37, 1958) was dissolved in cc.of benzene and treated with 2 g. of thionyl chloride.

The mixture was refluxed under anhydrous conditions for 2 hours. Thesolvent was evaporated under reduced pressure, the residue was againdissolved in 20 cc. of benzene and the solution evaporated to dryness,to make certain the total absence of thionyl chloride. The crude 16,8carboxylic acid chloride was treated with 2 cc. of diethylamine in 50cc. of benzene. The reaction mixture was left overnight at roomtemperature, then an aqueous solution of sodium carbonate was added. Theresulting emulsion was extracted with ether, the extract dried oversodium sulfate and evaporated to dryness. Crystallization frommethanol-water afforded 165-(diethyl carbamyl)-A17a-pregnen-3B-ol-20-one 3aacetate. M.P. l34l36 C.; [@1 66 (CHCI EXAMPLEXXIX l g. of A -pregnen-3fl-ol-20-one-l6B-carboxylic acid 3- acetate wastreated following the technique described in Example XXVIII, except thatdiethylamine was substituted by lpiperidine thus alfording16,8-(l-piperidyl-carbo11yl)- A -17a-pregnen-3,B-ol-20-one 3-acetate.

.12 EXAMPLE XXX 1 g. of A -17a-pregnen-3/3-ol-20-one-l6fi-carboxylicacid 3-acetate was treated in accordance with the method described inExample XXVIII except that diethylamine was substituted by morpholinethus tfurnishing 16,6-(4- morpholin-o carbonyl)-A-17a-pregnen-3/3-ol-20-one 3- acetate.

EXAMPLE XXXI 1 g. of A -17a-pregnen-3/3-ol-2O-one-IGB-canboxylic acid3-acetate was treated with thionyl chloride in accordance with ExampleXXVIII. The lofl-carboxylic acid chloride thus obtained was dissolved in50 cc. of benzene and 5 cc. of ammonium hydroxide were added. The formedprecipitate was filtered 01f, washed with benzene and dried undervacuum. Recrystallization from methanol-water afforded 16B-carbamyl-A-l7u-pregnen-3p-ol-20-one 3- acetate. M.P. 210-212 C.; [04],; 110 (CHClEXAMPLE XXXII A solution of 1 g. of the acetate of A-l7a-pregnen-3pol-20-one-l 6fl-carboxylic acid chloride in 50 cc. ofbenzene was treated with 5 cc. of N,N-diethylaminoethyl amine and thereaction mixture was left for 60 hours at room temperature. After theusual isolation technique there was obtained16p-(N',N'-die'thylaminoethyl carhamyl)- A -17a-pregnen-3fi-ol-20-one3-acetate. The methiodide, prepared by treatment of the amide withmethyl iodide showed M.P. 204-206 C.; [M 103 (MeOH).

In another experiment there were used 15 cc. of N,N- diethylaminoethylamine -for l g. of the acid chloride and the react-ion mixture was keptat room temperature for 8 days. There was thus obtained16fi-(N',N'-diethylaminoethyl carbamyl)-A -17fi-pregnen-3B-ol-20-one3-acetate, which upon treatment with methyl iodide gave thecorresponding methiodide which has a M.P. 263266 C.; [aJ +156 (MeOH).

EXAMPLE XXXIII To a solution of mg. of 16fi-(N',N'-diethylaminoethylcarbamyl)-A -17ot-pregnen-3p-ol-20-one. B-acetate in 15 cc. of methanolthere were added 3 drops of a 2% methanol solution of sodium hydroxideand the mixture kept at room temperature for 48 hours. It was thendiluted with water, extracted with ethyl acetate and the organic extractwashed to neutral, dried and evaporated to dryness. The residue wasreacetylated with acetic anhydride in pyridine solution; there was .thusobtained 16;?- (N,N-diethylaminoethyl carbamyl -A -pregnen-3 [3-01-20-one 3-acetate, identical to that obtained in the preceding example byusing an excess of amine.

EXAMPLE XXXIV 1 g. of A -17u-pregnen-3 8-ol-2O-one-l6 8-carboxylic acid3-acetate was treated in accordance with Example XXVIII but diethylaminewas substituted by N-methyl aniline thus yielding16(3-(N-methyl-N-phenyl carbamyl)- A -l7u-pregnen-3fl-ol-20-one3-acetate.

Treatment of this compound with 3 drops of 2% methanolic solution ofsodium hydroxide, in accordance with the method of the precedingexample, gave the corresponding 17/3-isorner.

EXAMPLE XXXV 3 g. of 16,B-carbamyl-A -17ot-pregnen-3B-ol-2O-0ne 3-acetate obtained according to Example XXXI in 100 cc. of methanol weretreated with 1 g. of potassium carbonate in 5 cc. of water. The mixturewas refluxed for 0.5 hour, then poured into ice water, the precipitatecollected, washed with water, and dried, thus producing a crude productwhich upon recrystallization from methylene chloride-ether afforded16/3-carbamyl-A -17a-pregnen-3pol-20-one.

When applying the above method to 16,8-(diethylcarbamyl)-A-17a-pregnen-3fl-ol-20mne 3-acetate, 16,6-(l-pi- '13 peridyl carbonyl)-A-17ot-pregnen-3fl-ol-20-one 3-acetate, 16,8 (4 morpholino carbonyl) A17a pregnen 3 3- ol-20-one 3-acetate, 16,8-(N,N-diethylaminoethylcarbammorpholino carbonyl)-A -17a-pregnen-3fl-ol-20-one, 16,8-

(N',N-diethylaminoethyl carbamyl) -A -17a-pregnen-3 [3- ol 20 one, and16,8 (N methyl N phenyl carbamyl)-A -17a-pregnen-3fi-ol-20-one.

EXAMPLE XXXVI To a solution of 2.4 g. of 16,8-carboxy-A -Not-pregnen-3,20-dione in 360cc. of ethyl alcohol, 67.5 cc. of 0.1 N sodiumhydroxide solution were added. This mixture was evaporated to drynessunder high vacuum and then dried, under high vacuum, at 110 during 1hour. Then 50 cc. of anhydrous benzene and 25 drops of anhydrouspyridine were added, at room temperature. After cooling this solution at0, cc. of oxalyl chloride were added with stirring. The mixture wasallowed to react during 3 hours at 0. The solvents were then evacuatedunder high vacuum.- To this dry material 60 cc. of anhydrous benzenewere added and then, drop by drop, at 0, 80 cc. of ammonium hydroxidewere added with stirring. This mixture was allowed to react for 3 hoursat 0 and 'hours' at room temperature. Extraction with ethyl acetatefollowed by a chromatography on silica gel gave, by elution with amixture of chloroform-methanol (80-20), the

pregnene-3,20-dione.

Further treatment of these compounds with 2% methanolic potassiumhydroxide, as described in Example XXXIII, gave the corresponding17;8-isomers.'

EXAMPLE XXXVII A solution of 800 mg. of 16fi-carbamyl-A -17a-pregnen-3,20-dione in 40 cc; of ethyl acetate was shaken with 50 mg. of 5%palladium charcoal catalyst in a hydrogen atmosphere, until the gasuptake corresponded to one mol. The catalyst was filtered oil and thefiltrate evaporated to dryness. Recrystallization from methanol afforded16B- carbamyl-17a-allopregnane-3,20-dione.

Following the same technique there were hydrogenated '16B-diethylcarbamy1-A -17a-pregnene-3,20-dione, 16,8-(1- piperidylcarbonyl A 17apregnene 3,20 dione, 16B- (4 morpholino carbonyl) A 17a pregnene 3,20dione, 16,8-(N',N'-diethylaminoethyl carbamy1)-A -pregnene-3,20-dione,and l6 3(N-methyl-N-phenyl carbamyl)- A -pregnene-3,20-dione givingrespectively 16B-diethyl carbamyl-17ot-allopregnane-3,20-di0ne,l6fl-(l-piperidyl carbonyl-17a-allopregnan-3,20-dione,16,8-(l-morpholino carbonyl)-l7a-allopregnane, 3,20-dione,16,8-(N,N'-diethylaminoethyl carbamyD-allopregnane-3,ZO-dione, and 16,8-(N-methyl-N-phenyl carbamyl)-allopregnane-3,20 dione.

EXAMPLE XXXVIII Following the technique delineated in Example XXXVII,there were hydrogenated 800 mg. of 16B-carbamyl-A-17a-pregnen-3fl-ol-2O-one to give I6fi-carbamyl-17a-allopregnan-3j8-ol-20-one.

By the same method were treated 16/8-diethyl carbamyl- A-l7a-pregnen-3fl-ol-2O-one. l6fi-(l-piperidyl carbonyl)- A-17a-pregnen-3/3-ol-20-one, 16/3-(4-morpholino-carbonyl) A 17a pregnen35 ol 20 one, 16,8 (N',N'- diethylaminoethyl carbamyl) A 17a pregnen 3dol- 20-one, and 16B-(N-methyl-N-phenyl carbamyl)-A-l7apregnen-3fi-ol-20-one, furnishing correspondingly 16 8-diethylcarbamyl-1741-allopregnan-3fl-ol-20-one, 16fi-(1-piperidylcarbonyl-17a-allopregnan-3B-ol-20-one, -(4- morpholinocarbonyl)-17a-allopregnan-3fl-ol-20-one, 16B- (N,N'-diethylaminoethylcarbamyl)-17a-al1opregnan-3,B- ol -20-one, and 16fi-(N-methyl-N-phenylcarbamyl)-l7aallopregnan-3fl-o l-20-one.

EXAMPLE XXXIX 500 mg. of 16B-carbamyl-A -17ot-pregnen-3B-ol-20-one in 5cc. of pyridine were treated with 1 cc. of propionic anhydride. Thereaction mixture was left overnight at room temperature, then pouredinto ice water, the formed precipitate filtered oif, washed with waterand dried. Recrystallization from acetone-hexane aiforded IGB-carbamyl-A-17u-pregnen-3 3-ol-20-one 3-propionate.

Following the above technique, there were treated the starting materialslisted below with the acylating agent indicated, furnishing thecorresponding products hereinafter set forth:

Starting Compound Aeylating agent Products l6fi diethylcall)amyl-A-17a-pregnen-3B-ol 20-one Benzoylehloride3-b6I1Z0ate0il6fi-diethylcarbamyl-A -17 .pregne .3fl. 1 2() one. DCaproic anhydride -capr0ate of lfifl-diethyl carbam l-A -17a- .35. 1 20.

one. -3 -o1-20-one C 010 ent 1 to ionic an- 3-cycl0pentylpropionate of16B-(1-piperidyl earbonyD-N- 16/3 (1 piperldyl carbonyl) A 17a pregnen By ey p p pregnenafiomoonel Do i Propionic anhydride 3-glraopliglateof16B-(1-piperidyl carbonyl)h nd-pregnen- -o- -one. 16B-(4morph01inocarbonyl)-A -17a-pregnen-3B-o1-20-one Caproic anhydride 3-c iti prfggeof 16fl-(4-morpho1ino carb0nyl)-A 17a-pregnen- -oone. Do pi ni a hydrid-g D g at f16fl-(4morpho1ino carbonyl)-A 17a-pregnen- -o one.16,9-(N,N-diethylarrunoethy1 earbamyl)-17a-a11opregnan- Benzoyl chloride-benz0ate 0i16B-(N,N-diethylamiuoethy1carbamyD-Ha- 3fl-ol-20-one.allopregnan-Sfl-ol-ZO-one.

D Cyclopentylpropionie an- 3-cyelopenty1prop1onate of16B-(N,Nd1ethylammoethy1 h dride.carbamyl)'17a-all0pregnan-3fi-ol-20-one. ldfl-(N-methyl-N-phenylcarbamyl)-17a-al1opregnan-3fl-ol- Propionic anhydride 3-prop1onate oflfifl-(N-methyl-N-phenyl carbamyD-fla- 20-one. allopregnan-aB-ol-ZO-one.

Do Benzoyl chloride 3-benzoate of IGB-(N-methyl-N-phenylcarbamyD-Ha-allon pregnan-3B-ol-20-one.

lfifi-diethylcarbamyl17a-a1l0pregnan-3fl-ol-20-one Caproic anhydride 3c2%pr0ate of 16Bd1ethyl earbamyl-l7a-a1lopregnan-3fl-ol- -one. DCyclopentylpropionic an- 3-cyc1opentylpr'opionate of ,IGB-diethylcarbamyl-17a-a1l0- hydride. pregnan-3fl-ol-20one lfifl-(l-piperidylcarbonyl)-17a-all0pregnan-3B-o1-20-one Propionic anhydride3-rsigoliigiaaoteeoilfifl-(l-plpendylcarbony1)-17a-a1lopregna -o n DoCaproic anhydride 3-caproate of ldfl-(l-piperidylcarbonyD-Ua-aIIopregnanv 3fl-o1-20one.

1 5 EXAMPLE XL wherein Z is a member of the group consisting of a doublebond and a saturated linkage between C-4 and C5; R and R are selectedfrom the group consisting of hydrogen, a lower alkyl, an amino loweralkyl, a lower alkylamino lower alkyl, a dilower alkylamino lower alkyl,an aryl and an aralkyl group containing up to 8 carbon atoms and R and Rtogether with the nitrogen atom form a heterocyclic radical selectedfrom the group consisting of piperidino, morpholino, pyrrolidino andpiperazino. 2. A compound of the following formula:

wherein Z is a member of the group consisting of a double bond and asaturated linkage between -4 and C; R and R are selected from the groupconsisting of hydrogen, a lower alkyl, an amino lower alkyl, a loweralkylamino lower alkyl, a dilower alkylamino lower alkyl, an aryl and anaralkyl group containing up to 8 carbon atoms and R and R together withthe nitrogen atom form a heterocyclic radical selected from the groupconsisting of piperidino, morpholino, pyrrolidino and piperazino.

3. l6,8-carbamyl-A -l7a-pregnene-3,20-dione.

4. A compound of the following formula:

, lb wherein Y is a member of the group consisting of a double 'bond anda saturated linkage between C-5 and C6; R and R are selected from thegroup consisting of hydrogen, a lower alkyl, an amino lower alkyl, alower alkylamino lower alkyl, a diloweralkylamino lower alkyl, an aryland an aralkyl group containing up to 8 carbon atoms and R and Rtogether with the nitrogen form a heterocyclic radical selected from thegroup consisting of piperidino, morpholino, pyrrolidino, and piperazino;R is selected from the group consisting of hydrogen and a hydrocarboncarboxylic acyl group of less than 12 carbon atoms.

5. A compound of the following formula:

- of piperidino, mor-pholino, pyrrolidino, and piperazino;

R is selected from the group consisting of hydrogen and a hydrocarboncarboxylic acyl group of less than 12 carbon atoms.

6. 16fl-diethyl carbamyl-A -l7a-pregnen-3B-ol-20-one 3- acetate.

7. 16,8 (N,N' diethylaminoethyl-carbamyl)-A-17upregnen-3fl-ol-2O-one-3-acetate.

9. 16B (N,N dieth-ylaminoethyl carbamyl)-A -l7B- pregnen-3fi-ola20-one3-acetate.

10. A compound of the following formula:

wherein Z is a member of the group consisting of a double bond and asaturated linkage between C4 and C-5; R and R are selected from thegroup consisting of hydrogen, a lower alkyl, an amino lower alkyl, alower alkylamino lower alkyl, a dilower alkylamino lower alkyl, an aryland an aralkyl group containing up to 8 carbon atoms and R and Rtogether with the nitrogen atom form a heterocyclic radical selectedfrom the group consisting of piperidino, morpholino, pyrrolidino andpiperazmo.

11. A compound of the following formula:

t R K\/ VQ wherein Y is a member of the group consisting of a doublebond and a saturated linkage between C- and C-6; R and R are selectedfrom the group consisting of hydrogen, a lower alkyl, an amino loweralkyl, lower alkylamino lower alkyl, a diloweralkylamino lower alkyl, anaryl and an aralkyl group containing up to 8 carbon atoms and R and Rtogether with the nitrogen form a heterocyclic radical selected from thegroup consisting of piperidino, morpholino, pyrrolidino, and piperazino;R

18 is selected from the group consisting of hydrogen, and a hydrocarboncarboxylic acyl group of less than 12 carbon atoms.

13. A compound of the following formula:

"W O R wherein Y is a member of the group consisting of a double bondand a saturated linkage between C-5 and C-6; R and R are selected fromthe group consisting of hydrogen, a lower alkyl, an amino lower alkyl, alower alkylamino lower alkyl, a diloweralkylamino lower alkyl, an aryland an aral kyl group containing up to 8 carbon atoms, and R and Rtogether with the nitrogen form a heterocyclic radical selected from thegroup consisting of piperidino, morpholino, pyrrolidino, and piperazino;-R is selected from the group consisting of hydrogen and a hydrocarboncarboxylic acyl group of less than 12 carbon atoms.

14. 16a-carbamyl-A -pregnen-3B-ol-20-one. 15. 16a(N,N'-diethylaminoethyl-carbamyl)-A -pregnen-3fi-ol-20-one.

16. 1 6a-carbarnyl-A -pregnene-3,ZO-dione. 17. l6u-(diethyl-carbamyl) -A-pregnene-3 ,ZO-dione. 18. 1 6w(pipenidinoecarbonyl)-A-pregnene-3,20-dione. 19. l6ot-carbamyl-A -l7u-pregnen-3B-ol-20-oneacetate. 20. 16a-carbamyl-A -l7a pregnene-3,2O-dione.

References Cited by the Examiner UNITED STATES PATENTS 3,066,136 11/1962 Crabbe 260--239.5

OTHER REFERENCES Fieser and Fieser, Steroids, 1959, page 566, ReinholdPub. Corp., New York.

LEWIS GOTTS, Primary Examiner.

1. A COMPOUND OF THE FOLLOWING FORMULA: